Ph.D. THESIS ABSTRACT SYNTHESIS, STEREOCHEMISTRY AND ...

“BABES-BOLYAI” UNIVERSITY CLUJ-NAPOCA
FACULTY OF CHEMISTRY AND CHEMICAL ENGINEERING
ORGANIC CHEMISTRY DEPARTMENT
Ph.D. THESIS ABSTRACT
SYNTHESIS, STEREOCHEMISTRY AND PROPERTIES OF SOME NEW
SPIRANE-TYPE COMPOUNDS CONTAINING 1,3-DIOXANE UNITS,
AND OF SOME NEW MACROCYCLES WITH PHENOTHIAZINE UNITS
Ph.D. STUDENT SCIENTIFIC ADVISER
RADU GROPEANU Prof. Univ. Dr. ION GROSU
JURY
PRESIDENT
Prof. Dr. CATALIN POPESCU – Head of the Chemistry-Physics Department, Faculty of
Chemistry and Chemical Engineering, Cluj-Napoca
REVIEWERS
Prof. Dr. THOMAS J.J. MÜLLER– Karl Ruprecht University, Heidelberg (Germany)
Prof. Dr. IONEL MANGALAGIU – Al. I. Cuza University, Iasi
Prof. Dr. SORIN MAGER – Babeş-Bolyai University, Cluj-Napoca
Defense: November 10 th
-2005-

Radu Gropeanu – PhD Thesis Abstract
CONTENTS:
PART A.
SYNTHESIS, STEREOCHEMISTRY AND PROPERTIES OF SOME NEW SPIRANE-
TYPE COMPOUNDS CONTAINING 1,3-DIOXANE UNITS
1. SYNTHESIS AND STREOCHEMICAL STUDY OF SOME NEW BENZO-SPIRANES
CONTAINING 1,3-DIOXANE UNITS
1.1. GENERAL ASPECTS CONCERNING THE STEREOCHEMISTRY OF 1,3-DIOXANE
SPIRANES
1.1.1. GENERALITIES
1.1.2. THERMODINAMIC AND KINETIC ASPECTS OF 1,3-DIOXANE RING
1.1.3. FLEXIBLE AND ANANCOMERIC 1,3-DIOXANE COMPOUNDS
1.1.4. CONFORMATIONAL ANALYSIS OF 2-ARYL-1,3-DIOXANE DERIVATIVES
1.1.5. STEREOCHEMISTRY OF SPIRO-COMPOUNDS WITH 6-MEMBERED RINGS
1.2. STEREOCHEMISTRY OF BENZO-1,3-DIOXANES
1.2.1. STEREOCHEMISTRY OF CYCLOHEXENE
1.2.2. BENZO-1,3-DIOXANE
1.3. ORIGINAL CONTRIBUTIONS
1.3.1. INTRODUCTION
1.3.2. SYNTHESIS AND STRUCTURAL ASPECTS IN SOLUTION
1.3.3. STEREOCHEMICAL ASPECTS OF BENZO-SPIRANES IN SOLID STATE
2. SYNTHESIS, STEREOCHEMISTRY AND ADSORPTION STUDIES OF SOME NEW
(POLY)SPIRANES CONTAINING 1,2-DITHIOLANE UNITS
2.1. GENERAL ASPECTS OF 1,2-DITHIOLANE
2.1.1. MAIN METHODS OF SYNTHESIS
2.1.2. STEREOCHEMISTRY OF THE 1,2-DITHIOLANE CYCLES
2.1.3. ADSORPTION PROPERTIES OF ORGANOSULPHUR COMPOUNDS
2.2. ORIGINAL RESULTS
2.2.1. INTRODUCTION
2.2.2. SYNTHESIS AND STEREOCHEMISTRY OF SPIRANES CONTAINING
MARGINAL 1,2-DITHIOLANE UNITS
2.2.3. ADSORPTION STUDIES
3. CONCLUSIONS
4. EXPERIMENTAL
4.1. GENERALITIES
4.2. SYNTHESIS AND DESCRIPTION OF THE COMPOUNDS
REFERENCES
LIST OF THE SYNTHESIZED COMPOUNDS
PART B.
SYNTHESIS AND PHYSICO-CHEMICAL PROPERTIES OF SOME NEW
MACROCYCLES CONTAINING 10H-PHENOTHIAZINE UNITS
1. INTRODUCTION
2. ORIGINAL RESULTS
2.1. IODO-SUBSTITUTED PHENOTHIAZINES
2.1.1. LITERATURE DATA ON THE IODO-PHENOTHIAZINES
2.1.2. SYNTHESIS OF IODO-PHENOTHIAZINE DERIVATIVES
2.1.3. PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS OF HALO-
PHENOTHIAZINES
2.2. FERROCENO-PHENOTHIAZINE MACROCYCLES
2.2.1. SYNTHESIS OF FERROCENE-PHENOTHIAZINE DERIVATIVES
2

Radu Gropeanu – PhD Thesis Abstract
2.2.3. SYNTHESIS OF MACROCYCLES CONTAINING FERROCENE AND
PHENOTHIAZINE UNITS
2.2.4. PHYSICO-CHEMICAL PROPERTIES OF THE SYNTHESIZED DYADS AND
TRIADS
2.3. SHAPE-PERSISTENT MACROCYCLES
2.3.1. INTRODUCTION
2.3.2. THE STRATEGY OF THE PHENOTHIAZINE-ACETYLENE MACROCYCLES
SYNTHESIS
2.3.3. THE SYNTHESIS OF THE PRECURSORS
2.3.4. THE CYCLIZATION ATTEMPT
2.3. PHENOTHIAZINE CORONANDS
2.3.1. GENERALITIES
2.3.2. SYNTHESIS OF MACROCYCLES STARTING FROM DIPHENOL
DERIVATIVES
2.3.3. THE SYNTHESIS OF THE INTERMEDIATES
2.3.4. SYNTHESIS OF CORONANDS HAVING PHENOTHIAZINE UNITS
3. CONCLUSIONS OF PART B
4. EXPERIMENTAL
REFERENCES
LIST OF THE SYNTHESIZED COMPOUNDS
KEYWORDS:
1,3-dioxane; benzo-1,3-dioxane; (poly)spirane; benzo-spirane; 1,2-dithiolane; cyclic disulfide;
iodo-phenothiazine; oligophenothiazine; ferrocene; Suzuki cross-coupling; Negishi crosscoupling;
Sonogashira cross-coupling; McMurry reductive coupling; cyclophane; coronand;
stereochemical analysis; adsorption on gold; adsorption on gold nanoparticles.
INTRODUCTION
The research work presented in this Ph.D. Thesis is conducted in two main fields
represented one side by the study on the synthesis, stereochemistry and properties of some new
derivatives of saturated and unsaturated heterocycle spiranes, and on the other side by the
synthesis and properties of new phenothiazine oligomers and macrocycles containing
phenothiazine units.
The first subject of the thesis was developed at “Babes-Bolyai” University Cluj-Napoca
in the research group I am belonging, while the investigations concerning the second subject of
my thesis were made in the research group of Prof. Thomas Müller (Ruprecht Karls Universität
Heidelberg) during a 12 months research stage financed by a DAAD fellowship (iodophenothiazines,
oligophenothiazenes and ferrocene-phenothiazine macrocycles), and in Cluj-
Napoca (phenothiazine coronands).
The research concerning the saturated six-membered ring heterocycles was first oriented
to the study of the stereochemistry of benzo-spiranes by means of NMR and X-ray diffraction.
Another direction of the research was represented by the synthesis of some new spiranes
containing 1,2-dithiolane units as cyclic disulfides, and the adsorption of these on the gold
surface in order to obtain 2D and 3D monolayers of (poli)spiranes.
The objectives of the research on phenothiazines were dedicated to the synthesis of
oligophenothiazines as well as ferrocene-phenothiazine derivatives, including ferrocenephenothiazine
macrocycles. Also, the obtainment of phenothiazine coronands as possible
selective cation receptors was investigated and realized.
3

Radu Gropeanu – PhD Thesis Abstract
PART A.
SYNTHESIS, STEREOCHEMISTRY AND PROPERTIES OF SOME NEW
SPIRANE-TYPE COMPOUNDS CONTAINING 1,3-DIOXANE UNITS
1.1. INTRODUCTION
1,3-Benzodioxanes represent an interesting motif in applied chemistry. They were reported as
agrochechemical fungicides, 1 biocides, 2 pesticides 3 and herbicides. 4 Some 1,3-benzodioxanes
were tested for pharmacological activity and were found to have antiinflammatory activity and
low toxicity, 5 or antiinflammatory, analgesic, mucolytic, and antipiretic activity. 6 The
unsaturated spiranes occur in the acidic degradation of steroides 7 or are a part of the skeleton of
saponine of Ruscus aculeatus L. 8 Despite the various and numerous reports, few papers are
dealing with the stereochemistry of 1,3-benzodioxanes. 9 This prompted us to investigate in
details the stereochemistry of a series of benzocondensed dioxa-monospiranes and of a
dibenzocondensed tetraoxa-dispirane.
1.2. SYNTHESIS AND STRUCTURAL ASPECTS IN SOLUTION
The synthesis of one of the target compounds (2) was previously described. 10 We have
obtained the benzo-spiranes 11 by ketalization of several cyclohexanones with salicylic alcohol in
fair to good yields (Scheme 1).
4
1
1
OH
OH
OH
Benzene, reflux
OH
2 O O
APTS
- 4 H2O
O
R
Benzen, reflux
APTS
- H2O
R Product Yield
H 2 40
8-CH3 3 38
8-R(+)-CH3 4 42
9-CH3 5 40
9-C(CH3)3 6 40
5
7 O
4
3
10
8 6
11 O 9 O
1
16
O 15
12 14
13
2
7
Scheme 1
10
2
11
1
O
6
3
4
2-6
7
O
5
+
9
R
8
10
8
7
4
5
O
6
3
11 O 9 O
1
2
12
16
O 15
14
13
The reactions equilibra were shifted toward products by using anhydrous sodium sulfate
to remove the reaction water. The flash chromatography (silica gel, petroleum ether:ethyl
acetate=10:1) was used to purify the crude products.
The 1 H-NMR spectra of the products present the signals corresponding to the
cyclohexane ring (δ = 1-2.15 ppm), which are slightly shifted to higher fields than the
1
Simon,W.E.J. Can. Pat. Appl. CA 2117503 AA, 1995.
2
Simon, W.E.J. Eur. Pat. Appl. EP 645373 A1, 1995.
3
a) Anderson, M.; Brinnand, A.G.; Woodall, R.E. Eur. Pat. Appl. EP 525877 A1, 1993. b) Anderson, M.; Brinnand,
A.G.; Woodall, R.E. Eur. Pat. Appl. EP 469686 A1, 1992.
4
Enomoto, M.; Nagano, H.; Haga, T.; Morita, K.; Sato, M. Jpn. Kokai Tokkyo Koho JP 63275580 A2, 1988.
5
Dauksas, V.; Gaidelis, P.; Brukstus, A.; Ramanauskas, J.; Labanauskas, L.; Gasperaviciene, G.; Jautakiene, I.;
Lapinskas, V.; Lauzikiene, N. Khim-Farm. Zh. 1989, 23(8), 942.
6
Torre, A. Eur Pat Appl EP 272223 A1, 1988.
7
a) Koga, T.; Nogami, Y. Tetrahedron Lett. 1986, 27, 4505. b) Izawa, H.; Katada, Y.; Sakamoto, Y.; Sato, Y.
Tetrahedron Lett. 1969, 10, 2947.
8
Lapin, H.; Sannie, C. Bull. Soc. Chim. Fr. 1955, 1552.
9
Brink, M. Monatsh. Chem. 1973, 104, 619.
10
Chondhury, P.K.; Almene, J.; Foubelo, F.; Yus, M. Tetrahedron 1997, 53, 17373.
11
Gropeanu, R.A.; Grosu, I. “SYNTHESIS AND STEREOCHEMISTRY OF SOME NEW SPIRO BENZO-1,3-
DIOXANE DERIVATIVES” Central European Journal of Chemistry 2005, submitted.
8
4

Radu Gropeanu – PhD Thesis Abstract
corresponding signals of the starting cyclohexanones. Beside of these, the spectra present the
aromatic protons (δ = 6.70-7.20 ppm) and the 1,3-dioxine methylene (δ = 4.80-4.90 ppm).
Monospirane 2 has a flexible structure, both 4[H]-1,3-dioxine (B) and cyclohexane (A)
rings are flipping (Scheme 2). The 4[H]-1,3-dioxine prefers the chiral half-chair conformations
with C6 and O5 out of the plain of the aromatic ring. The flipping of the heterocycle determines
an enantiomeric inversion (I and III; II and IV are enantiomers). The flipping of the cyclohexane
ring represents diastereomeric equilibrium, structures I and III exhibit the O-C6H4- moiety in
equatorial orientation while structures II and IV have the O-CH2-C6H4- group in equatorial
position (refereed to the cyclohexane ring).
I
O
B
O
O
B
O
A
A
1 (A)
2 (B) 4 (B)
3 (A)
O
B
O
O
B
O
III IV
2
Scheme 2
These possibilities have as result a fast equilibrium between the four conformers at room
temperature in solution, which was shown by the 1 H-NMR spectrum. The 1,3-dioxine methylene
(position 4) gives rise to a singlet at δ 4.81 ppm, and the axial and equatorial cyclohexane
protons could not been distinguished, the corresponding signals being mediated.
Compounds 3-6 have semiflexible structures, the substituted cyclohexane ring is
anancomeric (the R group is holding group and exhibits equatorial orientation) and the 4[H]-1,3dioxine
ring is flipping (Schemes 3). These compounds show cis (scheme 16: VIa and VIb;
scheme 17: VII and VIII) and trans isomers (scheme 3: Va and Vb; scheme 4: IX and X). R and
O-C6H4- are considered as references. At the same time the chirality (planar) of the 4[H]-1,3dioxine
ring determines the chirality of the compounds and the flipping of the heterocycle
determines the enantiomeric inversion for 3-5 (Va Vb; VIa VIb) and the diastereomeric
equilibrium for 6 (VII VIII; IX X). The cis and trans structures could not be isolated as
single isomers and the compounds were investigated as mixture of isomers.
Va
O
B
O
O
B
O
A
R
A
O
A
B
pR B pS
O
R
R
trans
Vb
B
VIa pS cis
5,6
VIb pR
Scheme 3
O
A Me
O
A Me
B
*
O
(R) B
B (R) *
O
pR pS
VII cis
VIII
(R) *
O
B
O
A
Me
B
O
B
O
II
*
(R)
IX pS trans
4
X pR
Scheme 4
O
B
O
A
Me
A
A
A
R
5

Radu Gropeanu – PhD Thesis Abstract
The 1 H-NMR spectra of 3-6 show many signals in the part of the spectrum corresponding
to the protons of the cyclohexane ring due to frozen flipping of this ring and to the differentiation
of axial and equatorial orientations. The singlet corresponding to the CH2 protons of the
heterocycle is more shielded for the trans isomer (∆δ 3-6 = δ cis - δ trans = 0.05-0.10 ppm).
The diastereoisomers have only very small differences of the physico-chemical
properties, so it was difficult to separate them and duly characterize. After the column
chromatography separation, only samples enriched in one isomer could been obtained. The ratio
between isomers was determined comparing the 1,3-dioxine methylene signals and the results
are presented in Table 1.
Table 1. Ratio of diastereomers in enriched fractions and the chemical shift of the corresponding
1,3-dioxine methylene (CDCl3, 300 MHz, rt)
Entry Compound
Ratio of diastereomers (DIA 1:DIA 2)*
First sample Last sample
Chemical shift (δ, ppm)
DIA 1 DIA 2
1 3 82:18 27:73 4.80 4.89
2 4 80:20 34:66 4.80 4.89
3 5 100:0 24:76 4.80 4.87
4 6 58:42 42:58 4.80 4.89
* The two isomers were formally named DIA 1 and DIA 2 tacking into account the Rf values.
The exception was brought by the dispirane obtained by ketalization of 1,4-cyclohexanedione,
which presents two well distinguished and separable isomers: 7 (trans) and 8 (cis).
Dibenzo-dispiro derivatives 7 and 8 exhibit three stereogene elements, two 4[H]-1,3dioxine
rings with planar chirality 12 and the differently substituted cyclohexane ring which
determines cis and trans isomers. Cis and trans isomers of 6 were separated by flash
chromatography and were investigated as single compounds. The chirality of the heterocycles
determines like (pRpR; pSpS) and unlike (pRpS = pSpR) structures (Schemes 5 and 6). Cis
isomer (XI-XIII) exhibits the reference groups (–C6H4-O-) in axial-equatorial orientations and
the flipping of the cyclohexane ring is an homomeric equilibrium while the flipping of 4[H]-1,3dioxine
rings determines the diastereoisomeric equilibrium. Trans isomer (XIV-XIX) exhibits
the reference groups either in axial-axial, either in equatorial-equatorial orientations. The
flipping of the cyclohexane or of the 4[H]-1,3-dioxine rings represents diastereoisomeric
equilibria.
B
O
O
B
O
O
O
A
B'
O
B
O
A
O
B'
O
B'
O
A
O
B'
O
pRpR
B
O
pSpR
B
O
pSpS
XI XII
XIII
A A
A
A
XI
O
B'
O
pRpR
B
O
B
O
XII
B'
A O
B'
O
8
Scheme 5
pSpR
O
B
O
A O
B'
O
XIII pSpS
12 Eliel, E.L.; Wilen, S.H. Configuration and Conformation of Cyclic Molecules. In: Stereochemistry of Organic
Compounds (1994), John Wiley and Sons, Inc., New York, p.726.
6

Radu Gropeanu – PhD Thesis Abstract
Cis and trans isomers are flexible compounds and the flipping of the central cyclohexane ring
and of the heterocycles renders in equilibrium all possible isomers (enantiomers and
diastereoisomers; cis: XI-XII, trans: XIV-XIX). The rt 1 H NMR spectra of trans and cis exhibit
only singlets for the protons of 4[H]-1,3-dioxine rings (7-trans: δ4,13 = 4.85 ppm; 7-cis: δ4,11 =
4.86 ppm). The spectra display a singlet for the protons of the cyclohexane ring of the trans
isomer and overlapped multiplets for those of cis one (7: δ7,8,15,16 = 2.03 ppm; 8: δ7,8,15,16 = 1.93-
2.09 ppm; Schemes 5, 6).
B
O
B
O
O
O
XIX (aa)
O
A
B'
O B
O
A
O
B'
O
B'
O
A
O
B'
O
pRpR
XIV (ee)
B
O pSpR
XV (ee)
B
O
XVI (ee)
pSpS
A
A O
B'
pRpR
O
B
B
O
O
A
A O
B'
O
pSpR
XVIII (aa)
7
Scheme 6
B'
B
O
O
XVII (aa)
A
A O
B'
O
pSpS
The variable temperature 1 H NMR experiments run with 7 and 8 (Figure 1 and 2) show
the freezing of the flipping of the rings at low temperatures (that determines a higher number of
signals in the NMR spectra). Two net coalescence points for 7 isomer (Tc = 224 K for the signals
belonging to the protons of the cyclohexane ring, Tc’ = 220 K for the protons of the heterocycles)
and one coalescence point for cis isomer [the signals corresponding to the 4[H]-1,3-dioxine ring
(Tc = 217 K)] could be measured.
5.2
5.0
4.8
4.6
4.4
4.2
4.0
Figure 1. 1 H-NMR spectra of 7 recorded at different temperatures (CDCl3, 300 MHz)
3.8
O
O
3.6
3.4
O
293 K
233 K
225 K
224 K
223 K
220 K
217 K
213 K
O
3.2
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
7

Radu Gropeanu – PhD Thesis Abstract
5.2
5.0
4.8
4.6
4.4
4.2
4.0
3.8
3.6
O
O
293 K
233 K
218 K
217 K
216 K
213 K
Figure 7. 1 H-NMR spectra of 8 recorded at different temperatures (CDCl3, 300 MHz)
3.4
1.3. STEREOCHEMICAL ASPECTS OF BENZO-SPIRANES IN SOLID STATE
The solid-state molecular structure was determined for 7 (Figure 8) using X-ray
diffractometry on a monocrystal. The cyclohexane ring exhibits chair conformation having the
O-Ph formal substituents in equatorial orientation, while the O-CH2 substituents are disposed in
axial positions. The 1,3-dioxine rings have a twisted chair conformation, with the O2 and O14,
respectively, outside the plane of the benzene (Figure 9). The initial assumption that the oxygen
and spirane carbon atoms are in the same plane was close to reality, taking into account that the
dihedral angle between O1-C10-O9 plane and O13-C14-O22 plane is 3.35°. The two benzene
rings are oriented in anti conformation and are parallel (dihedral angle 1.471°).
Figure 3. ORTEP 13 drawing of 7
The package of molecules in the monocrystal caused an interesting stacking pattern by
the interaction between one benzene ring and one hydrogen atom belonging to the methylene
group of the 1,3-dioxine moiety of a neighboring molecule (Figure 4). The distance between this
hydrogen and the centre of the neighboring phenylene is 2.66 Å.
13 Farrugia, L.J. J Appl Cryst 1997, 30, 565.
O
3.2
O
3.0
2.8
2.6
2.4
2.2
2.0
1.8
1.6
8

Radu Gropeanu – PhD Thesis Abstract
Figure 4. Mercury drawing of two neighboring molecules in the monocrystal of 7
2. SYNTHESIS, STEREOCHEMISTRY AND ADSORPTION STUDIES OF SOME NEW
(POLY)SPIRANES CONTAINING 1,2-DITHIOLANE UNITS
2.1. The Synthesis
The synthesis 14,15 of the target (poly)spiranes involves as the first step the (a)cetalization
reaction of various carbonyl compounds with 2,2-bis(bromomethyl)-1,3-propanediol (Scheme 7).
The equilibrium of the reaction was shifted toward products by removing the water by azeotropic
distillation of the reaction water with the solvent (benzene or toluene).
R
R1
HO
Br benzene, reflux R1 O
O +
R2 HO
Br APTS R2 O
9a-d
10
1 - 8 hrs.
11-15
O +
HO
Br benzene, reflux
R
O
HO
Br pTSA
O
16a-c
10
3 - 10 hrs.
17-19
O O
20
HO
HO
Br
Br
CHO
+
HO
Br benzene, reflux
CHO HO
Br pTSA
3 - 10 hrs.
O O
22a, o-formyl
22b, m-formyl
+ 2
10
10
benzene, reflux
pTSA
6 hrs.
Br
Br
Br
Br
Scheme 7
Br
Br
O
O
Br Br
R1 R2 Carbonyl Compound Product
CH 3 CH 3 9a 11
H C 6 H 5 9b 12
H 1-C 10 H 7 9c 13
CH 3 C 6 H 5 9d 14
CH 3 1-C 10 H 7 9e 15
R Ketone Product
H 16a 17
C 6 H 5 16b 18
CH 3 16c 19
21
O
O
O
O
23: ortho
24: meta
The assigned structures were confirmed by NMR spectra.
For the obtainment of the target cyclic disulfides 25-32 we have modified a procedure
previously reported by Chorbadijev et al 16 for the synthesis of dome acyclic disulfide derivatives
(Scheme 8) via substitution of a halide atom with disodium disulfide (previously generated from
14
Gropeanu, R.A.; Woiczechowski-Pop, A.; Tintas, M.; Turdean, R.; Grosu, I. Studia Univ. Babes-Bolyai, Ser.
Chim. 2005, 50, 247.
15
Gropeanu, R.A.; Tintas, M.; Pilon, C. ; Morin, M.; Breau, L.; Turdean, R.; Grosu, I. “SYNTHESIS,
STEREOCHEMISTRY AND ADSORPTION STUDIES OF NEW (POLY)SPIRANES CONTAINING 1,2-
DITIOLANE UNITS “Monatshefte für Chemie 2005, submitted.
16
Chorbadjiev, S.; Roumian, C.; Markov, P. J. Prakt. Chem. 1977, 319, 1036
Br
Br
Br
Br
9

Radu Gropeanu – PhD Thesis Abstract
sulphur and sodium hydroxide). In order to increase the yield of the cyclic disulfide via
suppression of polymer generation we greatly reduced the reagent concentrations (from 0.5 M to
0.03M).
Br
Br
R 1
R 2
EtOH, reflux 6 NaOH + 6 S 2 Na2S2 + Na2S2O3 + 3 H2O
1 hr.
O
O
Br
Br
+ Na2S2
11: R1 = CH3, R2 = CH3
12: R 1 = H, R 2 = C 6H 5
14: R 1 = CH 3, R 2 = C 6H 5
15: R 1 = CH 3, R 2 = 1-C 10H 7
EtOH, reflux R O
4 h O
1
R 2
9 10 1
2
S
8
5 S
3
7 6 4
25: R1 = CH3, R2 = CH3
26: R 1 = H, R 2 = C 6H 5
27: R 1 = CH 3, R 2 = C 6H 5
28: R1 = CH3, R2 = 1-C10H7
R
O
O
Br
Br
+ Na2S2 EtOH, reflux 4 h
12
R
11
13 14
O
8
O
15 1
5
2
S
S
3
10 9 7 6 4
O
17: R = H
18: R = C 6H 5
19: R = CH 3
O
O O
Br
Br
+ Na2S2
29: R = H
30: R = C 6H 5
31: R = CH 3
EtOH, refl ux
17
S
18 19 20 21
O
22 23
O
24 1
2
S
4 h S
16
14
15 13
O11
12 10
8 O
9 7
5
6 4
S
3
21 32
Scheme 8
The target (poly)spiranes afforded after the flash chromatography in fair to good yields (35-74%
for 25-31 and 27% for 32). The mass spectra and NMR spectra of the products confirmed the
assigned structures.
2.2. The Stereochemistry of (Poly)spiranes Containing 1,2-Dithiolane Units
Monospirane 25, dispirane 29 and tetraspirane 32, that are showing symmetrical substituted sixmembered
rings, exhibit flexible structures. The six-membered rings prefer the chair
conformation. Taking into account the literature data concerning the conformation of 1,2dithiolane
ring we propose for this heterocycle, in our compounds, the envelope conformer with
the spirane atom out of the plane. The flipping of the 1,3-dioxane (A) and 1,2-dithiolane (B)
rings in 25 (Scheme 9) renders equivalent in NMR positions 1 with 4 and 6 with 10. The 1 H-
NMR spectrum at rt do not discriminate the axial and equatorial orientations of the protons or of
the similar group and exhibits only three singlets (δ1,4 = 2.94, δ6,10 = 3.71, δ8-Me = 1.37 ppm).
Compound 29 shows four isomers of configuration, due to the chirality of the spiranes units with
six-membered rings 17,18 and to the syn or anti arrangement of the peripheral rings for di or
polyspirane skeleta. 19,20,21 The flipping of 1,3-dioxane, cyclohexane and 1,2-dithiolane rings
(Scheme 10) determines the conformational equilibrium of all the possible isomers. The 1 H-
NMR spectrum of 29 presents only two singlets for the protons of 1,3-dioxane and 1,2-dithiolane
rings (δ1,4 = 2.96, δ6,15 = 3.74 ppm). The flipping of the peripheral 1,2-dithiolane rings and of the
middle six-membered cycles of tetraspirane 32 determines the equilibrium of all possible
isomers. The 1 H-NMR spectrum of 32 is very simple and shows only three singlets (δ1,4,15,18 =
3.00, δ6,13,19,24 = 3.76, δ9,10,21,22 = 1.87 ppm).
17
Grosu, I.; Mager, S.; Ple, G.; Horn, M. J. Chem. Soc., Chem. Commun. 1995, 167.
18
Grosu, I.; Mager, S.; Ple, G. J. Chem. Soc. Perkin. Trans. 2 1995, 1351.
19
Grosu, I.; Mager, S.; Ple, G.; Mesaros, E. Tetrahedron 1996, 52, 12783.
20
Opris, D.; Grosu, I.; Toupet, L.; Ple, G.; Terec, A.; Mager, S.; Muntean, L. J. Chem. Soc., Perkin Trans. 1 2001,
2413.
21
Terec, A.; Grosu, I.; Condamine, E.; Breau, L.; Ple, G.; Ramondenc, Y.; Rochon, F.D.; Peulon-Agasse, V.; Opris,
D. Tetrahedron 2004, 60, 3173.
10

Radu Gropeanu – PhD Thesis Abstract
12
11
A
A
O
O
H3C
9
10
O
O A
2
1
S
3
B S
5 4
8 7 6
CH3
H 3C
B
B
syn (P)
O
O
III
C
B
anti (P)
II
CH 3
O
O
C S
S
C S
S
A
A
B
B S
S
A
B
B
25
Scheme 9
O
O
B
anti (M)
IV
H3C
H 3C
O
O
CH3
CH 3
S
C S
A
A
O A
O
A
A
S
B S
B S
S
1 2
S
S
13
A
14
15
O
O B
8 7 6
9 syn (M)
3
C S
5 4 A
A
O
O B
anti (P)
C S
C
A
O
O B
syn (P)
10 I II III
29
Scheme 10
Spiranes 26-28, with differently substituted 1,3-dioxane units exhibit anancomeric 1,3dioxane
rings. The flipping of the heterocycle is shifted towards the conformation in which the
most bulky substituent is placed in equatorial position (Scheme 11; Ph for 26 and Me for 27 and
28; for similar cases see references 22,23,24 ). The flipping of the 1,2-dithiolane ring renders
equivalent in NMR positions 6 and 10. However the 1 H-NMR spectra of 26-27 are more
complex and exhibit different signals for the equatorial and axial protons at positions 6 and 10
and for the axial and equatorial methylene groups of the 1,2-dithiolane ring (e.g. compound 26:
δ6a,10a = 3.90, δ6e10e = 4.13, δCH2a = 3.49, δCH2e = 2.71 ppm).
R
O
O
V VI
2
R 1
S
S
R
O
O 2
R 1
A
B
A
A
S
S
O
R O 2
R 1
O
O
R 1
R 2
2
1
9
3
10 B
5 4 A
8 7 6
VI'
B
A
VI"
26: R 1 = H, R 2 = C6H5
27: R 1 = C6H5, R 2 = CH3
28: R 1 = 1-C10H7, R 2 = CH3
Scheme 11
O
O
S
B S
O
B
syn (P)
O
A
B
anti (M)
22 Anteunis, M.J.O.; Tavernier, D.; Borremans, F. Heterocycles 1976, 4, 293.
23 Mager, S.; Grosu, I. Stud. Univ. “Babes-Bolyai”, Ser. Chemia 1988, 33, 47.
24 Grosu, I.; Plé, G.; Mager, S.; Mesaros, E.; Dulau, A.; Gego, C. Tetrahedron 1998, 54, 2905.
S
B S
III
IV
S
C S
C S
S
C S
S
11

Radu Gropeanu – PhD Thesis Abstract
Dispiranes 30 and 31 display semiflexible structures (Scheme 12), the cyclohexane ring
is rigid, the substituent of this cycle being an efficient “holding group” and the 1,3-dioxane and
1,2-dithiolane parts are flipping and render in equilibrium the possible stereoisomers (VII-X).
The 1 H-NMR spectra do not differentiate the axial or equatorial orientation of the protons of the
heterocycles but exhibit different signals (singlets) for the diastereotopic positions 6 and 15 (30:
δ6 = 3.81, δ15 = 3.85, δ1,4 = 3.04 ppm and 31: δ6 = 3.71, δ15 = 3.76, δ1,4 = 2.98 ppm). The
diastereotopicity of positions 6 and 15 is observed in 13 C-NMR spectra, too (30: δ6 = 66.32, δ15 =
66.50 ppm and 31: δ6 = 66.34, δ15 = 66.61 ppm). Position 6 is procis and position 15 is protrans
referred to the substituent at position 11.
12
11
R 1
R 1
13
A
10
A
1 2
S
14
15
O
O B
3
C S
5 4
8 7 6
9
syn (M)
VII
O
O
C
B
S
C S
B
B
R 1
R 1
A
O B
O
syn (P)
anti (M) anti (P)
30, 31
VIII
X
Scheme 12
Figure 5. 1 H-NMR spectrum of 30 (CDCl3, 300 MHz, r.t.)
2.3. ADSORPTION STUDIES
A. Adsorption on planar gold surfaces
Individual gold (111) surfaces were immersed in 1 mM ethanolic solutions of the cyclic
disulfides, 29 to 32, for at least 24 hours in order to form monolayers. The monolayers were then
analyzed by reflective IR spectroscopy. The relevant fragments of the spectra of two compounds
are depicted in Figures 6 and 7. The wave numbers of the vibrational bands of their IR spectra
are presented in Table 2. The assignment of the vibrational bands and the direction and
magnitudes of the vibrational dipole moments were obtained from Hartree-Fock calculations
done with Gaussian 98® software.
O
O
H6, H15
A
15
1
6
4
S
S
O
IX
O
C
B
C S
S
C S
S
H1, H4
12

Radu Gropeanu – PhD Thesis Abstract
Absorbance
0.0008
0.0006
0.0004
0.0002
0.0000
-0.0002
( ) ( q )
2700 2800 2900 3000 3100 3200
Wavenumbers (cm -1 )
1
O
O
S
S
Absorbance
0.001
0.000
-0.001
900 1000 1100 1200 1300 1400 1500 1600 1700 1800
Wavenumbers (cm -1 )
Figure 6. IR reflexion-absorption spectrum of a monolayer of 31 adsorbed on a gold (111) surface (relevant
fragments)
Absorbance
0.0002
0.0000
3
S
O O
S O O
2700 2800 2900 3000 3100 3200
Wavenumbers (cm -1 )
S
S
Absorbance
0.0005
0.0000
900 1000 1100 1200 1300 1400 1500 1600 1700 1800
Wavenumbers (cm -1 )
1
O
O
3
S
O O
S O O
Figure 7. IR reflexion-absorption spectrum of a monolayer of 32 adsorbed on a gold (111) surface (relevant
fragments)
The widths of the bands at half-height in the IR spectra are in the range of 20-40 cm -1
which suggests that the molecules are disordered on the gold surface. Also, the methylene
νa(CH2) band at 2926-2930 cm -1 (that is present in all samples) is indicative of a liquid like
monolayer. This disorder is probably due to the complex and relatively rigid structure of the
molecules which results in a large distance between the adsorbed molecules and thus few
stabilizing inter-adsorbate interactions that usually results in self-assembly. Although the
monolayer is not very organized, some information on the orientation of the adsorbed molecules
could be drawn from the IR investigations. Our analysis of the IR spectra are based on the
direction of the vibrational dipole moments obtained from a computational chemistry calculation
and the infrared surface selection rule for adsorbates on metallic substrates 25 which states that a
vibrational mode is IR active if there is a component of its dipole moment perpendicular to the
surface.
Table 2. IR wave numbers (ν/cm -1 ) of the SAMs for each cyclic disulfide 29-32 on a gold (111)
surface
Assignment 29 30 31
32
νa(=C-H, Ar) - 3065 (weak) - -
νa(=C-H, Ar) - 3031 (weak) - -
νa(=C-H, Ar)
νa(CH3)
-
2961
3017 (weak) - -
a (weak) 2959 a
2958 2958 a (weak)
νa(CH2)
νs(CH3)
2928
-
2930
2874
2926 2926
a
2869 -
νs(CH2) 2857 2856 2857 2857
νa(C-O-C) 1096 1131 1154 1130
a
due to a small amount contaminant containing a methyl group
The analysis of the wave numbers and intensity of the vibrational bands of compounds 30
and 32 adsorbed on gold suggest that they adopt the orientations shown in Figures 19 and 20.
25 Greenler, R.G. J. Chem. Phys. 1966, 44, 310.
S
S
S
S
13

Radu Gropeanu – PhD Thesis Abstract
Also, it is likely that both compounds bind to the surface via at least two of their sulphurs, as
disulfides are known to dissociate upon adsorption on gold. 26
The absence of CH deformation bands between 1300 and 1400 cm -1 suggests that 32 is
not oriented perpendicular to the surface but is rather parallel to the surface. In this orientation
the C-H deformation modes of methylenes will have a low intensity. It is thus possible that
compound 32 is anchored to the surface by both 1,2-dithiolane rings. However, this would
require an important reorganization of the optimized structure shown in Figure 8.
a b c
Figura 8. Possible orientations of compounds 30 (a) and 32 (b) and (c) adsorbed on Au(111) suggested by the
analysis of its IR spectra.
B. Adsorption on gold electrodes and interaction with gold nanoparticles
The interaction between some (poly)spiranes having 1,2-dithiolane units and gold
nanoparticles (GNP) was studied for the beginning using UV-Vis spectroscopy. Thus, the UV-
Vis spectra of the organic ligands in chloroform and of the GNP (water solution) were recorded,
as well as the spectra of the samples obtained by mixing cyclic disulfides with GNP solution
(Figure 9). The main feature of the samples spectra is the decay of the plasmodic resonance peak.
For example, in short time (20 minutes) the absorbance in the 500-550 nm region of the spectra
was five times reduced in the case of interaction between 32 and GNP (Figure 9d). Also, the
electronic absorption peak of the organic ligand (330 mn) has disappeared (Figure 9c).
Absorbanta
0.12
0.11
0.10
0.09
0.08
0.07
0.06
0.05
0.04
440 460 480 500 520 540 560 580 600 620
λ(nm)
Absorbanta
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
100 200 300 400 500 600 700 800 900 1000
λ(nm)
Absorbanta
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
-0.5
200 300 400 500 600
λ(nm)
Absorbanta
0.042
0.040
0.038
0.036
0.034
0.032
0.030
0.028
0.026
0.024
0.022
Au+STS-1min
Au+STS-5min
Au+STS-20 min
0.020
440 460 480 500 520 540 560 580 600 620
a b c d
Figure 9. UV-Vis spectra of the a) water dispersion of GNPs, b) chloroform solution of 32, c) GNPs
functionalized with 32, and d) GNPs functionalized with 32, recorded at three different times
These facts suggest an aggregation process of the nanoparticles, which is sustained by the
transmission electronic microscope (80 kV) measurements (Figures 10).
a b c
Figure 10. Transmission electronic microscope image of the a) GNPs suspension, b) GNPs functionalized with
30, and c) GNPs functionalized with 32
26 Fenter, P.; Eberhardt, A.; Eisenberg, P. Science 1994, 266, 1216
λ(nm)
14

Radu Gropeanu – PhD Thesis Abstract
A method which is suitable for the study of the adsorption of the cyclic disulfides on the
gold surface is the cyclic voltammetry using a gold electrode as working electrode. After the
cleaning operations, the cyclic voltammetry of the standard system [K4Fe(CN)6 in 0.1 M KCl,
Figure 11a] was performed and compared with the cyclic voltammograms run with the gold
electrodes functionalized with each of cyclic disulfide 25-27, 30, 32. The absence of a redox
process has shown that the spirane monolayer adsorbed on the surface of the gold electrode acts
as a dielectric isolator (Figure 11b).
a b
Figure 11. Cyclic voltammogram of a solution of 3 mM K4Fe(CN)6 in 0.1 M KCl using a) bare gold electrode
(10 mV/sec) and b) urface functionalized gold electrode with 32 (50 mV/sec)
31 has two cyclic disulfide units per molecule and, therefore, was tested for the
functionalization of the gold electrode surface with GNP. Two methods of the preparation were
tried: Method A: the electrode treated with the organic ligand was immersed in the GNP solution,
and Method B: the electrode was immersed into the solution obtained by mixing of GNP with
organic ligand at different pH values (5.5, 7 and 11).
I / mA
I / mA
0.04
0.03
0.02
0.01
0.00
-0.01
-0.02
-0.03
0.06
0.04
0.02
0.00
-0.02
-0.04
0.0 0.1 0.2 0.3 0.4 0.5 0.6
Potential /V vs. Ag/AgCl
0.0 0.1 0.2 0.3 0.4 0.5 0.6
Potential / V vs. Ag/AgCl
-0.6 -0.4 -0.2 0.0 0.2 0.4 0.6
a b
Figure 12. Cyclic voltammograms of a) a solution of 3 mM K4Fe(CN)6 in 0.1 M KCl (buffered at pH
5.5) using surface functionalized gold electrode with 32 and GNP (10 minutes immersion, pH 7, by
Method A (50 mV/sec)), and b) a solution of 3 mM K4Fe(CN)6 in 0.1 M KCl (buffered at pH 7) using
surface functionalized gold electrode with 32 and GNP (pH 7) by Method B (50 mV/sec)
These functionalized electrodes were subjected to cyclic voltammetry of the standard
solution. The results showed us that only the Method B run at pH 7 was successful (Figure 12),
the voltammograms presenting a reversible redox process. Comparing the voltammograms, we
can remark that for the GNP-32-modified gold electrode the current maxima are more than two
times higher that the corresponding peaks for the non-functionalized gold electrode, meaning
that the modification of the surface is increasing the electron transfer between solution and
electrode.
I / mA
0.025
0.020
0.015
0.010
0.005
0.000
-0.005
-0.010
I / mA
0.0 0.1 0.2 0.3 0.4 0.5 0.6
0.15
0.10
0.05
0.00
-0.05
-0.10
Potential / V vs. Ag/AgCl
Potential / V, vs. Ag/AgCl
15

Radu Gropeanu – PhD Thesis Abstract
PART B.
SYNTHESIS AND PHYSICO-CHEMICAL PROPERTIES OF SOME NEW
MACROCYCLES CONTAINING 10H-PHENOTHIAZINE UNITS
1. INTRODUCTION
Phenothiazines belong to a pharmaceutically important class of heterocycles, 27 and due to
their pharmacological efficacy they are applied in a broad range as sedatives, tranquilizers,
antituberculotics, antipyretics, antitumor agents, bactericides and parasiticides. 28 They are also
able to cleave DNA upon photochemical induction. 29 As a consequence of a low oxidation
potential, these tricyclic nitrogen-sulfur heterocycles readily form stable radical cations and a
key role of their physiological activities can be attributed to this circumstance. 30 An interesting
feature of phenothiazines is the fact that the first oxidation step is reversible. 31 Thus,
phenothiazine derivatives have become spectroscopic probes in molecular and supramolecular
arrangements for photoinduced electron transfer (PET) studies. 32
Our work in this field had the following goals:
- the synthesis of some new building blocks useful in the preparation of oligophenothiazines of
determined number of phenothiazine units
- the synthesis of phenothiazine-ferrocene dyads and triads and to study the electronic
communication between the redox-active units of the oligomers, and of ferrocene-phenothiazine
cyclophane
- the synthesis of phenothiazine-containing macrocycles (shape-persisted macrocycles, as well as
phenothiazine coronands).
2. ORIGINAL RESULTS
2.1. SYNTHESIS OF IODO-PHENOTHIAZINE DERIVATIVES
The corner stone of our strategies was 10-alkyl-3,7-dibromo-10H-phenothiazine (1),
which is readily available from commercially 10H-phenothiazine (1) in two steps: the first step is
represented by an alkylation in the position 10 (at the secondary nitrogen of the phenothiazine
27
Sainsbury, M. In Comprehensive Heterocyclic Chemistry, Vol. 3; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:
Oxford, 1984, 995
28
(a) Mietzsch, F. Angew. Chem. 1954, 66, 363. (b) Ionescu, M.; Mantsch, H. Adv. Heterocycl. Chem. 1967, 8, 83.
(c) Bodea, C.; Silberg, I. Adv. Heterocycl. Chem. 1968, 9, 321. (d) Valzelli, L.; Garattini, S. In Principles of
Psychopharmacology; Clark, W. G., Ed.; Academic Press: 1970, 255. (e) Okafor, C. O. Heterocycles 1977, 7, 391.
(f) Eckstein, Z.; Urbanski, T. Adv. Heterocycl. Chem. 1978, 23, 1. (g) Szabo, J. Chem. Heterocycl. Compd. USSR
(Engl. Trans.) 1979, 15, 291. (h) Albery, W. J.; Foulds, A. W.; Hall, K. J.; Hillman, A. R.; Edgell, R. G.; Orchard,
A. F. Nature 1979, 282, 793.
29
(a) Nishiwaki, E.; Nakagawa, H.; Takasaki, M.; Matsumoto, T.; Sakurai, H.; Shibuya, M. Heterocycles 1990, 31,
1763.
(b) Decuyper, J.; Piette, J.; Lopez, M.; Merville, M. P.; Vorst, A. Biochem. Pharmacol. 1984, 33, 4025. (c) Motten,
A. G.; Buettner, G. R.; Chignell, C. F. Photochem. Photobiol. 1985, 42, 9. (d) Fujita, H.; Matsuo, I. Chem. Biol.
Interac. 1988, 66, 27.
30
(a) Forrest, I.; Forrest, F. Biochim. Biophys. Acta 1958, 29, 441. (b) Iida, Y. Bull. Chem. Soc. Jpn. 1971, 44, 663.
(c) Moutet, J.-C.; Reverdy, G. Nouv. J. Chim. 1983, 7, 105.
31
For cyclovoltammetric and spectroscopic data of phenothiazine, see for example: Tinker, L. A.; Bard, A. J. J. Am.
Chem. Soc. 1979, 101, 2316. (d) Padusek, B.; Kalinowski, M. K. Electrochim. Acta 1983, 28, 639. (e) McIntyre, R.;
Gerischer, H. Ber. Bunsen Ges. Phys. Chem. 1984, 88, 963.
32
(a) Duesing, R.; Tapolsky, G.; Meyer, T. J. J. Am. Chem. Soc. 1990, 112, 5378. (b) Jones, W. E. Jr.; Chen, P.;
Meyer, T. J. J. Am. Chem. Soc. 1992, 114, 387. (c) Brun, A. M.; Harriman, A.; Heitz, V.; Sauvage, J.-P. J. Am.
Chem. Soc. 1991, 113, 8657. (d) Burrows, H. D.; Kemp, T. J.; Welburn, M. J. J. Chem. Soc., Perkin Trans. 2 1973,
969. (e) Collin, J.-P.; Guillerez, S.; Sauvage, J.-P. J. Chem. Soc., Chem. Commun. 1989, 776. (f) Daub, J.; Engl, R.;
Kurzawa, J.; Miller, S. E.; Schneider, S.; Stockmann, A.; Wasielewski, M. R. J. Phys. Chem. A 2001, 105, 5655.
16

Radu Gropeanu – PhD Thesis Abstract
nucleus, Scheme 1). After the purification, the intermediate 3 is subjected to a bromination 33 to
afford the dibromo-phenothiazine 1 in excellent yield (98-99%, 69-79% overall yield).
8
7
H
9 10
N
6
S
5
2
1
4
2
3
1° 1.1 equiv. t-BuOK/1,4-dioxane
10 min. r.t., then 10 min. reflux
2° 1.1equiv. Alkyl-Br,
overnight, r.t.
60-80%
Alkyl
N
S
3
Scheme 1
2.1 equiv. Br 2 /AcOH
overnight, r.t.
98-99%
Alkyl
N
Br S
Br
1a, Alkyl = C 2 H 5
1b, Alkyl = n-C 6 H 13
The synthesis of the iodine-phenothiazines was realized 34 by a mono or a double Li-Br
exchange with nBuLi (Scheme 2) and a subsequent addition of iodine as electrophile.
Alkyl
N
2° 2.1 equiv. I
Br S
Br 2
I S
I
1a, Alkyl = C 2 H 5
1b, Alkyl = n-C 6 H 13
1° 2.1 equiv. nBuLi/THF/-78°C, 30 min.
Scheme 2
Alkyl
N
4a, Alkyl = C 2 H 5
4b, Alkyl = n-C 6 H 13
The iodine-phenothiazine structures of 4a, 4b were revealed by MS (each of the FAB-MS
spectra present the molecular peak, i.e. for 4b M = 535, and M/z = 534.9) and by NMR
measurements. The 1 H-NMR spectra have shown that the products are symmetrical substituted
phenothiazine derivatives, because of the occurrence in the aromatic region of three distinct
signals corresponding to the three pairs of phenothiazine aromatic protons.
One interesting feature of the iodo-derivatives is the upfield shifting of the signal of the
direct bounded carbon atom, compared to the bromine-substituted one. This shift is called
“heavy-atom effect”. For our compounds, the assigned chemical shift for this type of carbon
atom is 84.8 ppm (Figure 1).
200
175
8
9
150
a
N
I S
I
6
4
1
2
125
100
C3, C7
Figure 1. 13 C-NMR spectrum of 4b (CD3COCD3, 300 MHz, r.t.)
33 Bodea, C; Terdic, M. Studii si Cercet. Chimie, Acad. RPR Fil. Cluj 1962, 13, 81-87.
34 Sailer, M.; Gropeanu, R.A.;. Müller, T.J.J. “PRACTICAL SYNTHESIS OF IODO PHENOTHIAZINES. A
FACILE ACCESS TO ELECTROPHORE BUILDING BLOCKS” Journal Of Organic Chemistry 2003, 68, 7509.
75
50
25
0
17

Radu Gropeanu – PhD Thesis Abstract
The success of this reaction prompted us to investigate the possibility of the introduction
of one iodine atom in the phenothiazine molecule. This was realized by performing of a mono
Br-Li exchange by addition of only one equivalent of nBuLi in much longer time over of a more
diluted solution of 1 (Scheme 3).
Alkyl
N
2° 1 equiv. I
Br S
Br 2
I S Br
1b, Alkyl = n-C 6 H 13
1° 1 equiv. nBuLi/THF/-78°C, 30 min.
Scheme 3
Alkyl
N
5, Alkyl = n-C 6 H 13
The FAB-MS spectrum of 5 presents the molecular peak and its characteristic splitting of
the mono-brominated compounds (M/z = 488.7, 486.7, M=488). The NMR spectra show an
unsymmetrical substitution of the phenothiazine. Moreover, the 13 C-NMR spectrum presents a
signal due to a quaternary carbon atom at 84.8 ppm, assigned to the iodine-substituted carbon
atom.
The above described method generates bromo-iodo-phenothiazines useful in the
construction of oligophenothiazines. In order to obtain other unsymmetrical substituted iodophenothiazines
that contain other functional groups it was necessary to develop a different
method. Thus, we have relied on the Li-Br exchange and modified the electrophiles. Using 2
equivalents of nBuLi and two kind of electrophiles (in principle, the first one iodine, and as the
second one, other kind of electrophiles that can generate useful functions) could be obtained the
target phenothiazine derivatives. This idea was tested for the synthesis of 3-iodo-10-hexyl-10Hphenothiazine
(6, Scheme 4).
N
Br S
Br
1b
1º 1 equiv. nBuLi/THF/-78ºC
2º 1 equiv. H 2 O/THF/-78ºC
80%
Br
1º 2 equiv. BuLi/THF/-78ºC
2º 1 equiv. I 2 /THF/-78ºC
3º 1 equiv. H 2 O/THF/-78ºC
70%
N
S
7
Scheme 4
I
N
S
6
1º 1 equiv. BuLi/THF/-78ºC
2º 1 eqiiv. I 2 /THF/-78ºC
The direct transformation of 4b into 6 was performed by using one equivalent of iodine (as the
first added electrophile) and then water for quenching the dilithiated species of 4b. The
sequential transformation of 4b involved the exchange of one bromine atom with hydrogen, via
Li-Br exchange and the use of water as electrophile, and a subsequent replacement of the
remaining bromine from 7 with iodine, using the same Li-Br exchange. Comparing the yields,
these two pathways are quite similar, but the direct method brings some advantages: it reduces
the materials consumption, as well as the working time.
Having these on our mind, other electrophiles were also used in this procedure. Thus,
D2O, dry DMF, B(OMe)3 were added as second electrophiles to afford the corresponding nonsymmetric
substituted phenothiazines (Scheme 5).
N
88%
Br S
Br I S
E
4b 8-10
E
E+
1º 2 equiv. BuLi/THF anh./-78ºC
2º 1 equiv. I2/THF anh./-78ºC
3º 1 equiv. E+/THF/-78ºC la t.c.
8 9 10
D CHO
O
B
O
D2O DMF B(OMe)3 + pinacole
Scheme 5
N
18

Radu Gropeanu – PhD Thesis Abstract
The unsymmetrical structure of the phenothiazine derivatives 8-10 was shown by the NMR
spectra. For example, the 1 H-NMR spectrum of 9 presents distinct 6 signals for the phenothiazine
protons, as well as the signal corresponding for the formyl proton (δ 3-CHO = 9.80 ppm, Figure
2).
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
I S
CHO
Figure 2. 1 H-NMR spectrum of 9 (CD3COCD3, 300 MHz, r.t.)
6.0
N
5.5
The 13 C-NMR spectrum of 9 presents two characteristic signals: one corresponding to C-I (δ C7
= 85.81 ppm) and one for the formyl group carbon atom (δ C3’ = 190.28 ppm).
2.2. PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS OF HALO-
PHENOTHIAZINES
Halo-phenothiazines, as many other halo-derivatives, 35 undergo palladium-catalyzed
cross-coupling reactions. An extensively used method for the coupling of two Csp2 carbons is
represented by the Suzuki cross-coupling. 36 This reaction involves the interaction of one organic
halide and one organoboron compound, interaction mediated by Pd reduced species. This crosscoupling
reaction undergo in the presence of charged bases (Na2CO3, K2CO3, Na3PO4, KOH, and
alkoxides). 37,38
The synthesis of the phenothiazine boronic intermediates was previously described. 39
After generation of a mono or a double lithiated species by Li-Br exchange, an addition of
trimethylborate as electrophile, followed by the transesterification with pinacole, afforded the
phenothiazine mono- or bis-boronic esters (11a,b, 12, 13, Scheme 6). It was chosen the pinacole
ester due to their high stability. 40
In order to increase the selectivity, the reaction temperature was decreased. In the
synthesis of 15, despite the very good selectivity, the yield was not very good, after work-up
35 Poli, G.; Giambastiani, G.; Heumann, A. Tetrahedron 2000, 56, 5959.
36 Miyaura, N.; Suzuki, A. Chem. Rev.1995, 95, 2457.
37 Susuki, A. Acc. Chem. Res. 1982, 15, 178.
38 Miyaura, N.; Yamada, K.; Suginome, H.; Suzuki, A. J. Am. Chem. Soc. 1985, 107, 972.
39 Krämer, C.; Sailer, M.; Müller, T.J.J. Synthesis 2002, 1163.
40 Hoffmann, R.W.; Dresely, S. Synthesis 1988, 103.
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
19

Radu Gropeanu – PhD Thesis Abstract
some amounts of the starting materials were recovered. This was a sign that the temperature was
too low. However, the synthesis of 14 has afforded in good yield the desired triad.
N
1° 2 equiv. nBuLi/THF/-78°C
2° 2 equiv. B(OMe) 3 /THF/-78°C la t.c.
3° 2 equiv. pinacol
N
Br S
Br
65%
O
B S
B
O
4b O 11 O
Br
4b
N
S
7
1° 1 equiv. nBuLi/THF/-78°C
2° 1 equiv. B(OMe) 3 /THF/-78°C la t.c.
3° 1 equiv. pinacol
75%
1° 1 equiv. nBuLi/THF/-78°C
2° 1 equiv. B(OMe) 3 /THF/-78°C la t.c.
3° 1 equiv. pinacol
80%
Scheme 6
N
Br S
B
O
12 O
N
O
Br S
B
After the purification, only traces of the iodine-derivatives were isolated. The mass
spectra (FAB-MS) of 14 and 15 confirmed the assigned structures. The molecular peaks are
splitted; for example, for 14 (M = 1003) an usual distribution of M-2, M-1, M, M+1, M+2 peaks
characteristic to the dibrominated compounds occurred in the spectrum.
The 13 C-NMR spectra present characteristic peaks to the Csp2-Br at 114 ppm and no
signals corresponding to a Csp2-I bond.
Another dyad was synthesized in a different manner (Scheme 10), by an oxidative
coupling of two monolithiated phenothiazines.
N
2
Br S
Br
1b
1° 1 equiv. BuLi/-78°C/THF
2° dry CuCl 2
Br
Scheme 7
2.3. FERROCENO-PHENOTHIAZINE MACROCYCLES
Ferrocene represents an interesting redox-active material and, recently, the ferrocene core
has been used as a building-block in the construction of redox-active and responsive
macrocycles. 41
Thus, the prospect of integrating strongly coupled redox fragments like phenothiazines
and ferrocenes into conjugated chains could constitute a so far unknown class of redox
addressable molecular wires. In particular, the integration of these synthons into a fullyconjugated
macrocycle represented one of our main goals.
Palladium-catalyzed cross-coupling reaction were described to be an effective method in
the synthesis of ring-substituted ferrocenes. 42 From these methods, the Suzuki and the Negishi
41 a) Dinnebier, R.E.; Ding, L.; Ma, K.; Neumann, M.A.; Tanpipat, N.; Leusen, F.J.J.; Stephens, P.W.; Wagner, M.
Organometallics 2001, 20 (26), 5642, 5647; b) Beer, P.D.; Crowe, D.B.; Ogden, M.I.; Drew, M.G.B.; Main, B. J.
Chem. Soc., Dalton Trans.: Inorg. Chem. 1993, (14), 2107-2116; c)Beer, P.D.; Nation, J.E.; Brown, S.L. J.
Organomet. Chem. 1989, 377 (1), C23-C26; d) Bell, A.P.; Hall, D. J. Chem. Soc., Chem. Commun. 1980, (4), 163-
165; e) Plenio, H.; Aberle, C. Chem. Eur. J. 2001, 7(20), 4438-4446; f) Plenio, E.; Aberle, C.; Al Shihadeh, Y.;
Lloris, J.M.; Martinez-Manez, J.; Pardo, T.; Soto, J. Chem. Eur. J. 2001, 7(13), 2848-2861.
S
N
13
16
N
S
O
Br
20

Radu Gropeanu – PhD Thesis Abstract
couplings provided good results and, therefore, these were taken into consideration for our
purposes. Both of these methods involve the preparation of the dilithiated species of ferrocene 43
(17, Scheme 8).
Fe
2.5 equiv. nBuLi
1.25 equiv. TMEDA
Fe
Li
1° 2 equiv. B(OMe) 3
Fe
Li
2° pinacole or HO- /H2O 17
2 equiv ZnCl 2
Fe
19
ZnCl
ZnCl
Ar-X
Pd(0) catalyst
O
B
O
O
B
O
18a
Fe
Ar
Ar
where Ar = phenothiazine derivatives
Scheme 8
or
Fe
Ar-X
Pd(0) catalyst
The Suzuki cross coupling between 18a and 5 was performed using as catalyst
tetrakis(triphenylphosphine)palladium and typical conditions; the conversion of the ferrocene
18a was 100% (according to TLC), but the yield in the desired product was very low (about 1%).
The “product” proved to be a mixture of at least two ferrocene derivatives (according to NMR
and MS spectra). Using the MS (FAB+) spectrum we could assign the productsas mono-crosscoupling
products (with bromo-substituted phenothiazine as the major product and iodosubtituted
phenothiazine core as minor one) and the ferrocene mono-boronic-pinacole ester.
The first attempts of Negishi coupling have furnished the desired products in fair to good
yields. A series of Negishi couplings were performed in order to optimize the synthesis. The data
are presented in Scheme 9 and in Table 1.
The fact that the yields are rather modest could have two reasons:
a) the bis(lithiated) ferrocene was described to be not very stable in the presence of
ethers, such as THF or diethyleter. This means that is possible that the recovered ferrocene
appeared as a decomposition process of the 1,1’-dilithium-ferrocene.
b) the palladium catalyzed cross-coupling reactions between two rich electron systems
proceeds usually with low yields.
c) after all of the cross-coupling reactions there was recovered an insoluble, amorphous
brown material, which is most probably a mixture of polymers.
Analyzing the data, two conclusions could be drawn: the iodine-substituted
phenothiazines react better than the brominated ones, that is not surprising. Unfortunately, this
higher reactivity provides a larger amount of oligomeric by-products. Also, in the case of 4b
bis(ferrocenyl)-phenothiazine (26) was recovered as by-product, and this was not the case for
bromine-substituted phenothiazines. The second conclusion regards the catalysts: the best results
were obtained using Pd[(PPh3)4] for bromine-substituted phenothiazines, and PdCl2(PPh3)2 for
iodine-substituted phenothiazines, respectively.
A Negishi cross coupling at higher temperature (reflux) was also performed, but the yield
was lower than the reaction run at room temperature (see entry 9, Table 1).
42 a) Arnold, R.; Matchett, S.A.; Rosenblum, M. Organometallics 1988, 7, 2261; b) Enders, M.; Kohl, G.; Pritzkow,
H. J. Organomet. Chem. 2001, 622, 66-73; c) Enders, M.; Kohl, G.; Pritzkow, H. Organometallics 2002, 21, 1111-
1117.
43 a) Bishop, J.J.; Davison, A.; Katcher, M.L.; Lichtenberg, D.W.; Merrill, R.E.; Smart, J.C. J. Organomet. Chem.
1971, 27, 271; b) Knapp, R. ; Rehahn, M. J. Organomet. Chem. 1993, 452, 235-40
18b
OH
B
OH
OH
B
OH
21

Radu Gropeanu – PhD Thesis Abstract
19 +
[Pd]
2 R-PTZ-X (R-PTZ) n Fc Fc-PTZ-Fc
+
where: Fc = Fe PTZ =
20-25 26
Scheme 9
N
S
20 : R = Br, n = 1
21 : R = Br, n = 2
22 : R = H, n = 1
23 : R = H, n = 2
24 : R = I, n = 1
25 : R = I, n = 2
+ oligomers
X = Br, I
Table 1. The Negishi cross-coupling syntheses data; reagents, products, yields *
Entry [Pd] R X
Products
Obs.
Catalyst
Fc(PTZ-R)2 Fc-PTZ-R Fc-PTZ-Fc
1 Pd[(PPh3)4]
0.1%
H Br 9.4 11 - r.t., 3 days
2 Pd[(PPh3)4]
0.2%
Br I 2.8 21.9 - r.t., 3 days
3 Pd[(PPh3)4] Br Br 6.6 12.4 - r.t., 3 days
2.1%
(9.6) (18.6)
4 PdCl2(PPh3)2 Br Br 8.2 11.0 - r.t., 3 days
5%
(11.2) (15.1)
5 PdCl2(PPh3)2 Br I 21.6 31.1 - r.t., 3 days
3.9%
(24.3) (42.4)
6 Pd[(PPh3)4]
5%
I I 1 9.8 3 r.t., 4 days
7 Pd[(PPh3)4]
5%
I I 6 2 4 r.t., 5 days
8. Pd[(PPh3)4] Br Br 28.1 12.8 - r.t., 5 days
2.5%
(31.2) (14.2)
9. Pd[(PPh3)4] Br Br 15.3 11.8 - 1 hr. reflux,
2.5%
2 days r.t.
* Yields are reported to ferrocene; in brackets are presented yields calculated after subtraction of
the recovered ferrocene
Several attempts have been made to synthesize the desired macrocycle 27 directly from
19 and 4b using 1:1 stoichiometry and high dilution technique (Scheme 15). Unfortunately, the
isolated products were the corresponding dyads and triads (24-26), as well as some oligomers
(identified by MS-FAB+). In one case it was isolated a compound in a very low yield which
presents in mass spectra (ESI, FAB+) a peak corresponding to the molecular mass of the target
macrocycle (930).
19 + 4b
PdCl 2 (PPh 3 ) 2
r.t, 7-10 days
Fe
Scheme 10
N
S
S
N
27
Fe
22

Radu Gropeanu – PhD Thesis Abstract
This compound has a pronounced tendency to oxidize, revealed by the FAB+ technique
(in the spectrum appears a significant peak at M + 16). Unfortunately, due to the very small
amount and to the fact that the purity of the compound was not high, the NMR spectrum is
ambiguous and could not confirm the assigned macrocyclic-type structure.
2D-NMR experiments were performed in order to figure out the conformation adopted by
triads in solution. The most useful experiment is NOESY. Analyzing the spectra, could not been
identified cross-peaks between H 1 and H 4 , or H 6 and H 9 , respectively. This means that in solution
the triads are conformationally free, the electronic interactions between the two phenothiazine
units being too weak at room temperature in solution to prevent the free rotation of the ferrocene
core, having the iron as a pivot (Scheme 11).
R
R
H6 H6 H 9
H9
Hex
N
S
H4 H4 S
N
Hex
H 1
H 1
Fe
R
Hex
N
S
Fe
Scheme 11
S
N
Hex
R
R
R
S
N
Hex
S
N
Hex
Unfortunately, suitable crystals for X-ray structure analysis could not be grown for these
triads. Nevertheless, the dyads 20 and 22 furnished good crystals for analysis. ORTEP drawings
are depicted in Figure 1.
a b
Figure 1. ORTEP drawings of compounds 20 (a) and 22 (b).
Synthesis of macrocycles using the McMurry reductive coupling of carbonyl compounds
Another considered way for the synthesis of macrocycles is to convert the triad 21 into
the bis-formyl derivative and to close the macrocycle using the McMurry procedure for
transformation of aldehydes into alkenes.
The conversion of bromine-dyad 20, and dibromine-triad 21, respectively, was achieved
in good yields and on a gram scale using a lithium-bromine exchange and a subsequent
quenching of the lithiated species with dry DMF (Scheme 12).
(Br-PTZ) n Fc
20 : n = 1
21 : n = 2
where: Fc = Fe PTZ =
Scheme 12
(OHC-PTZ) n Fc
28 : n = 1; yield 80%
29 : n = 2; yield 65%
N
S
Fe
23

Radu Gropeanu – PhD Thesis Abstract
The formation of the formyl intermediates was proved by the MS spectra, in which occur
the corresponding molecular peaks. Also, the 1 H-NMR spectra present the characteristic singlet
signal of the formyl groups (28: δ 3-CHO = 9.79 ppm, 1H; 29: δ 3-CHO = 9.73 ppm, 2H).
The triad 29 furnished crystals suitable to X-ray diffraction analysis. In Figure 9 two
ORTEP drawings of 29 are presented. The two phenothiazine units are parallel and, surprisingly,
they adopted a syn orientation. The two cyclopentadienyl cycles are almost parallel and eclipsed.
a b
Figure 2. ORTEP drawings of compound 29, different views
We have chosen to test if the common reagent (TiCl4-Zn/Cu) is effective for our
substrates. Thus, we have attempted the McMurry coupling of 3-ferrocenyl-7-formyl-10-nhexyl-10H-phenothiazine
(28, Scheme 13) using the Mukaiyama’s procedure 25 and high dilution
conditions.
2
OHC
N
S
Fe
[Ti]/THF, Py
48 hrs., reflux
60%
28 30
Scheme 13
Fe
The separation of the products by silica gel column chromatography gave the desired
bis(ferrocenyl-phenothiazinyl)ethene (30) in 60% yield and a few amount of the reduced species
of the starting material.
This result prompted us to subject 29 to a reductive coupling reaction in the conditions
mentioned above, which, after work-up, afforded the desired macrocyclic product 31 (Scheme
14) in an excellent yield (73%). This excellent yield for a macrocyclization reveals the efficient
template effect of the titanium low-valent species.
OHC
OHC
N
S
S
N
29
Fe
[Ti]/THF, Py
reflux, 48 hrs
73.2%
Scheme 14
The 1 H-NMR spectrum of 31 presents, beside the signals characteristic to the two n-hexyl
groups and for the 1, 1’-disubstituted ferrocene, in the aromatic region the signals corresponding
S
N
Hex
S
N
Hex
N
S
31
N
S
Fe
Fe
24

Radu Gropeanu – PhD Thesis Abstract
to the two magnetic equivalent phenothiazine units, and the vinylic protons as a singlet (δ = 6.55
ppm) (Figure 3).
7.5
7.0
6.5
Figure 3. The 1 H-NMR spectrum of 31 (CDCl3, 300 MHz, r.t.)
6.0
5.5
5.0
4.5
The mass spectrum is in accordance with the assigned structure.
The X-rays analysis performed on monocrystal showed us that the vinylene bridge
presents the cis configuration, and that the two phenothiazine units lie in an anti orientation.
These phenothiazine units are a little beat twisted from a superposed arrangement, which is
preferred by the bis(phenothiazinyl)ferrocene derivatives (Figure 4). This fact suggests an
electronic communication between the two phenothiazines through the vinylene bridge. The
other atropisomer (with a syn orientation of the phenothiazinic units) could not been detected by
means of NMR spectrometry. Also, whilst there are described ferrocene macrocycles formed by
McMurry reductive coupling with the resulted vinylene bridge having both cis and trans
configurations, the trans isomer of 31 was not isolated.
a b
Figure 4. The ORTEP drawing of 31: a) view along a perpendicular axis to the cyclopentadienyl rings; b)
view along a parallel axis with the cyclopentadienyl rings
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
25

Radu Gropeanu – PhD Thesis Abstract
In order to suppress the electronic communication through the vinylene bridge, this was
catalytically reduced with molecular hydrogen in 1,2-dichloroetane to an ethylene bridge
(Scheme 15).
N
S
S
N
Fe
H 2 /10% Pd/C
r.t., 48 hrs.
98%
31 32
Scheme 15
The signals of the phenothiazinic protons in the 1 H-NMR spectrum of 32 are slightly
shifted up-field compared with the same protons of the 31. Also, the spectrum presents the signal
of the ethylene bridge (δ -CH2-CH2- = 2.71 ppm) as a singlet. Unfortunately, this compound
crystallizes in sharp needles, which are unsuitable for X-rays diffraction analysis. However, the
mass spectrum (FAB+) confirms the assign structure.
Phisyco-Chemical Properties of the Synthesized Dyads, Triads and Macrocycles
The dyads, triads, and the macrocycles were analyzed using cyclic voltammetry.
The results are presented in the Table 2. Due to the presence of two redox active units (ferrocene
and phenothiazine, respectively) our expectation was to find two oxidation waves. Indeed, the
cyclo-voltammograms of the dyads show two oxidation steps for the ferrocene and the
phenothiazine unit, respectively. The first step (0.57 V) is due to the ferrocene moiety, and the
second (1.01-1.02 V) to the phenothiazine rest, respectively (see Table 5, entry 1). In the case of
the bis(phenothiazinyl)ferrocene triads there are three redox waves (see Table 5, entry 2) despite
the fact that the molecules are symmetric. This fact can be a consequence of the electronic
communication between the two redox active phenothiazine centres. The electronic
communication can take place through the already oxidized ferrocene or through space by πstacking.
It was previously shown by the X-rays diffraction that in the solid state the two
phenothiazine moieties are superposed, most probably due to the π-stacking. In the case of
bis(ferrocenyl)-phenothiazine, two redox steps occur in the voltammogram, one due to the two
ferrocene units (two electrons process) and one (one electron process). This means that the two
feerocene are independent each other and, therefore, have the same redox potential.
One reason for the synthesis of the target macrocycles is to investigate this electronic
communication in solution because the two phenothiazine units are constrain at least partly to
superpose. The cyclo-voltammograms present the same electronic behavior like the triads. The
only difference in that the first oxidation step assigned to the phenothiazine units are at lower
potentials in the case of macrocycles. The gap between the oxidation steps of the phenothiazines
in the case of the non-cyclic triads is lower (0.111-0.169 V) than in the case of the macrocycles
(0.198 V for 31 and 0.238 V for 32, respectively). This fact can be take as a measure of
electronic communication (one phenothiazine unit playing the role of a rich-electron substituent
of the phenothiazine which oxidizes first) in the way that the greater the gap, the stronger the
communication. Not surprisingly, the strongest electronic communication is found in the
macrocyclic triads, especially for 32 in which the ethylene bridge is flexible (compared with the
vinylene bridge of the 31) and short enough to constrain the superposition of the phenothiazine
units in solution. This superposition is less probable in solution for the non-cyclic triads due to
the solvation of the molecule and to the free rotation around the ferrocene, respectively.
N
S
S
N
Fe
26

Radu Gropeanu – PhD Thesis Abstract
Table 2. Cyclic voltammetry data of some ferrocene-phenothiazine derivatives
Entry Cyclic Voltammogram E1/2 (V) Compound
1
2
3
4
5
I (µA)
I (µA)
I (µA)
I (µA)
I (µA)
4
2
0
-2
-4
-6
RG 27 a
100 mV/s, CH2Cl2
-8
1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0 -0,2 -0,4 -0,6
4
2
0
-2
-4
E (V)
-6
1,5 1,0 0,5 0,0 -0,5
3
2
1
0
-1
-2
-3
RG 27 b
100 mV/s
E (V)
-4
1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0 -0,2 -0,4 -0,6
2,0
1,5
1,0
0,5
0,0
-0,5
-1,0
-1,5
-2,0
-2,5
2
1
0
-1
-2
RG 19 c
CH2Cl2, 100 mV/s
E (V)
RG 68
CH 2 Cl 2 , 100 mV/s
1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0
E (V)
RG 73
CH2Cl2, 100 mV/s
-3
1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0
2.4. SHAPE-PERSISTENT MACROCYCLES
E (V)
0.572
1.020
0.549
0.946
1.115
0.576
1.042
0.563
0.904
1.102
0.521
0.798
1.036
Br
Br
Br
N
S
N
S
S
N
Fe
Fe
Fe Fe
A. Introduction
In the last decade a lot of shape-persistent macrocycles on the nanometre scale have been
synthesized and characterized. Due to a) the conformational rigidity, and b) to the fact that the
interior space is separated by the exterior these macrocycles were good candidates for various
supramolecular studies, such as organisation into and transport through porous molecular
crystals 44,45 or pattern formation at interfaces. 46 The basic structural type is represented by the
44 a) Henze, O.; Lenz, D.; Schäfer, A.; Franke, P.; Schlüter, A.D. Chem. Eur. J. 2002, 357-365; b) Werz, T.B.;
Staeb, T.H.; Benisch, C.; Rausch, B.J.; Rominger, F.; Gleiter, R. Org. Lett. 2002, 4, 339-342; c) Campbell, K.;
Kuehl, C.J.; Ferguson, M.J.; Stang, P.J.; Tykwinski, R.R. J. Am. Chem. Soc. 2002, 124, 7266-7267.
45 See, for example: Venkataraman, D.; Lee, S.; Zhang, J.; Moore, J.S. Nature 1994, 371, 591-593.
46 See, for example: a) Borissov, D.; Ziegler, A.; Höger, S.; Freyland, W. Langmuir 2004, 20, 2781-2784; b) Grave,
C.; Schlüter, A.D. Eur. J. Org. Chem. 2002, 3075-3098; c) Höger, S.; Bonrad, K.; Mouran, A.; Beginn, U.; Möller,
M. J. Am. Chem. Soc. 2001, 123, 5651-5659; d) Zhao, D.; Moore, J.S. Chem. Commun. 2003, 807-818.
N
S
S
N
N
S
S
N
S
N
Fe
Fe
27

Radu Gropeanu – PhD Thesis Abstract
phenylene-acetylene macrocycles, 47 which differ in the ring size (up to 5.5 nm) and in the sidechain
pattern. Several macrocyclic phenylacetylenes have been shown to have interesting
properties, such as self-association in solution, 48 the existence of liquid crystaline phases, 49 or the
capability to bind small molecules. 50
B. Synthesis of the Intermediates
The strategy is based on the sequential Sonogashira coupling reactions between dihalophenothiazines
and bis(ethynyl)-phenothiazine, which could be readily available from dihalophenothiazines.
The synthesis of bis(ethynyl)-phenothiazine (33) was previously described using
several ways: by Sonogashira coupling of dibromo-phenothiazine with trimethylsilyl-acetylene
(TMS-acetylene), by converting formyl-phenothiazines using Corey-Fuchs protocol or,
alternatively, the Ohira-Bestmann transformation. 51
It is well known that iodine derivatives react under mild conditions and easier than
bromine ones. As a consequence, we have performed this Sonogashira coupling using diiodophenothiazine
(Scheme 16); the reaction underwent smoothly, at room temperature, to afford the
bis(TMS-ethynyl)-phenothiazine (34) in 95% yield; the deprotection of TMS-groups was
achieved with TBAF/CH2Cl2.
I
N
S
4b
34
I
+ 2
TBAF / CH 2 Cl 2 + THF
r.t., 90 min.
95%
SiMe 3
4% PdCl 2 (PPh 3 ) 2 , 8% CuI
piperidine, r.t., 5 min.
98%
N
S
Me Si 3 SiMe3 34
N
S
33
Scheme 16
The 1 H-NMR of 33 presents the signal corresponding to the two 1-alkynyl protons (δ = 3.03
ppm).
The next step was the synthesis of the first precursor (35). The Sonogashira coupling
using the previously described conditions and the diiodo-phenothiazine 4b in 50% excess
(Scheme 17) afforded the diiodo-diethynylene-bridged phenothiazine triad 35 in fair yield (55%)
and some other products, most probably oligomers with 4 or more phenothiazine units.
4b + 33
4% PdCl 2 (PPh 3 ) 2 , 8% CuI
piperidine, r.t., 5 hrs.
55%
N
I
S
Scheme 17
47
Zhang, J.; Pesak, D.J.; Ludwick, J.L.; Moore, J.S.; J. Am. Chem. Soc. 1994, 116, 4227-4239.
48
a) Shetty, A.S.; Zhang, J.; Moore, J.S. J. Am. Chem. Soc. 1996, 118, 1019-; b) Tobe, Y.; Nagano, A.; Kawabata,
K.; Sonoda, M.; Naemura, K. Org. Lett. 2000, 2, 3265-, and references cited therein.
49
a) Zhang, J.; Moore, J.S. J. Am. Chem. Soc. 1994, 116, 2655; b) Collins, S.K.; Yap, G.P.A.; Fallis, A.G. Org. Lett.
2000, 2, 3189-.
50
Morrison, D.L.; Höger, S. Chem. Commun. 1996, 2313-14.
51
Krämer, C.S.; Zeitler, K.; Müller, T.J.J. Org. Lett. 2000, 2(23), 3723-3726, and references cited therein.
N
S
35
S
N
I
28

Radu Gropeanu – PhD Thesis Abstract
In order to reduce the ratio of oligomerization, we have tested the chemoselectivity of the
Sonogashira coupling using bromo-iodo-phenothiazine 5 with the selective obtaining of the
dibromo-analog of 35 (36, Scheme 18).
5 + 33
4% PdCl 2 (PPh 3 ) 2 , 8% CuI
piperidine, r.t., 24 hrs.
N
Br
S
Scheme 18
The yield was higher (72%), and the selectivity was high, and, as in the Negishi or
Suzuki coupling involving bromo-iodo-phenothiazine, only traces of the bromine-iodineethynylene-bridged
phenothiazine triad have been identified by mass spectrometry. Another
proof of the selective cross-coupling was brought by the 13 C-NMR spectrum of 36, in which does
not appear a signal corresponding to a Csp2-I carbon atom (signal at about δ 84-85 ppm).
The second precursor has to have two terminal ethynyl groups; the synthesis of 37 was
performed by a Sonogashira coupling between 35 and TMS-acetylene (Scheme 19), and a
subsequent deprotection of the TMS-protected intermediate 38 with TBAF.
35
+
SiMe 3
4% PdCl 2 (PPh 3 ) 2 , 8% CuI
piperidine, r.t., 1 hr.
38
TBAF/CH 2 Cl 2
r.t., 1 hr.
N
Scheme 19
In the 1 H-NMR spectrum of 37 the signal corresponding to the two terminal ethynyl
protons appears at 3.05 ppm.
C. The Cyclization Attempt
The cyclization was performed using the high dilution technique. An equimolar mixture
of the two precursors (35 and 37, respectively) was subjected to the Sonogashira cross coupling
reaction (Scheme 20). The 1 H-NMR spectrum of the main product is complex. In the aliphatic
region there are many signals due to at least two magnetically non-equivalent n-hexyl residues,
which is different as I would expect taking into consideration the 6 symmetrical substituted
phenothiazines from the target structure of the macrocycle. Also, these signals are shifted
downfield compared with those assigned to an n-hexyl core from a non-cyclic n-hexyl-10Hphenothiazine
derivative. In the aromatic region, the signals are spread between 5.5 and 9.5 ppm.
The spectrum of the sample extracted with THF looks more familiar with a spectrum of an nhexyl-10H-phenothiazine
derivative; however, in the aliphatic region the situation is the same as
previously described. In the aromatic region the signals are shifted downfield compared with the
precursors, and are more than 3 as I would expect for a symmetrical structure. This behavior can
be due to the free rotation of the phenothiazine units having the ethynyl units as pivots. In this
situation, there are two kinds of phenothiazine units: some with the N-n-hexyl rest oriented
outside the cycle, and the other having the N-n-hexyl rest oriented inside.
S
N
S
36
N
S
37
S
N
Br
S
N
29

Radu Gropeanu – PhD Thesis Abstract
35 +
37
4% PdCl 2 (PPh 3 ) 2 , 8% CuI
piperidine/THF, r.t., 48 hrs.
N
N
S
S
Scheme 20
Mass spectrometry experiments were performed in order to confirm the macrocyclic
structure. ESI-MS experiments have failed, whilst the MALDI gave a very small signal at
m/e=1831 (for the crude precipitate) and at m/e=1832 (for the THF extract). These values are in
the accepted range of measuring errors (± 0.1%, M=1830) and have shown the existence of the
target macrocycle.
In order to determine the electrochemical properties of the (poly)ethynylene triads, 35
was subjected to cyclic voltammetry determination. The results are presented in Table 5.
The cyclic-voltammogram of 35 presents one two-electrons oxidation step (0.92 V)
assigned to the two marginal phenothiazine units and an one-electron oxidation step (1.02 V)
corresponding to the internal phenothiazine moiety. The two-electron oxidation step shows that
the marginal phenothiazine units are not electronically connected and they are oxidizing
independent at the same potential.
Table 5. Redox properties and the cyclic-voltammogram of 35
CV Graph Oxidation step E1/2 (V) Structure
I (µA)
15
10
5
0
-5
-10
-15
RG 69
500 mV/s
1,4 1,2 1,0 0,8 0,6 0,4 0,2 0,0
E (V)
2.5. PHENOTHIAZINE CORONANDS
1 0.924
2 1.020
A. The Synthesis of the Intermediates
The conversion of 1 into 3,7-bis(hydroxymethyl)-10-ethyl-10H-phenothiazine (39) was
achieved in two steps. The first one has involved a Br-Li exchange with nBuLi, followed by the
addition of DMF as electrophile. The work-up with 5% HClaq afforded the diformyl-derivative
40 (Scheme 21). A subsequent reduction of 40 in mild conditions gave the first key intermediate
39.
N
S
S
N
38
N
I
S
S
S
N
N
N
S
S
N
I
30

Radu Gropeanu – PhD Thesis Abstract
N
1° 2.5 eq. nBuLi/THF/-78°C
Br S Br 2° 2.5 eq. dry DMF/-78°C
OHC S CHO 10 min., r.t. H C S CH
3° 5% HCl 2
2
aq
OH OH
1a
65-71%
40
99%
39
N
Scheme 21
NaBH 4 /i-propanol
The 1 H-NMR spectrum of 39 presents the three sets of signals in the aromatic zone, fact which
signifies the symmetrical substitution of the molecule. Besides of these, the signal corresponding
to the hydroxymethyl substituents appears in the spectrum (δ CH2 = 4.37 ppm, δ OH = 5.10 ppm,
Figure 14). The signals of the methylene and the hydroxyl of the hydroxymethyl groups are
splitted due to their coupling ( 3 J = 5.70 Hz).
The synthesis of the other key intermediate of our strategy also started from 1a through a
Br-Li exchange with nBuLi. In this case, the electrophile was trimethylborate, followed by the
addition of pinacole in order to generate the stable phenothiazine bis(boronic ester) (Scheme 22).
N
Br S
Br
1a
1° 2.5 eq. nBuLi/THF/-78°C
2° 2.5 eq. dry B(OMe) 3 /-78°C
3° 2.5 eq. dry pinacole, r.t.
50-53%
Scheme 22
The Suzuki cross-couplings of the n-hexyl-analog of 41 were presented above. In this
strategy two other coupling partners were considered: bromo-benzenes m-substituted with OH
and NH2, respectively. The synthesis of the ditopic intermediates for macrocyclization was
realized using standard conditions for the cross-coupling: Pd[PPh3]4 as catalyst, monoglym or
diglym/water, and an inorganic carbonate (Scheme 23). The column chromatography
purification (petroleum ether:ethyl acetate = 3:2) afforded the desired products 42 and 43, as well
as some small amounts of mono-substituted by-products.
O
B
O
N
S
41
O
B
O
+
Br
O
B
O
N
S
41
O
B
O
diglym:water = 2:1
Y reflux, overnight
S
Scheme 23
5% Pd[PPh 3 ] 4 , K 2 CO 3
N
Y
42: Y = OH , yield 60%
43: Y = NH2 , yield 65%
Y
The mass spectra of the products present the molecular peak (42: M/z = 613, 43: M/z =
611). The 1 H-NMR spectrum of 42 presents in the aromatic region partial overlapped 7 signals
corresponding to 14 protons. Also, the phenolic hydroxyl protons give in the spectrum a signal
having the integral for two protons. Also, the 13 C-NMR spectrum confirms the symmetrical
substitution of the phenothiazine core, due to the fact that in the aromatic region appear 12
signals corresponding to the 12 types of carbon atoms of the molecule.
The NMR spectra of 43 are almost similar to those of 42, with the difference that in the
1
H-NMR spectrum of 43 appears the signal corresponding to the 2 magnetic equivalent amino
groups (δ NH2 = 5.17 ppm).
B. Synthesis of Coronands Having Phenothiazine Units
The ditosylated pentaethyleneglycols were prepared by tosylation of the corresponding
polyethylene glycols (Scheme 24).
N
31

Radu Gropeanu – PhD Thesis Abstract
HO
O n
H
2.2 equiv. TsCl
NaOH/THF
2 hrs., 0-5°C
Scheme 24
The ditosyl derivatives were analyzed by NMR spctroscopy.
TsO
n = 1-5
ATTEMPT OF MACROCYCLIZATION OF 39
One attempt of the synthesis of phenothiazine-containing macrocycle starting from 39
was made using ditosylated triethyleneglycole (Scheme 25).
N
H2C S
CH2 OH 39 OH
N
O n
H2C S
CH2 O O O O
Conditions: 1° 2 eq. NaH/THF/reflux 1 hr.
2° 1 eq. diTs triethyleneglycole over 6 hrs/THF/reflux 48 hrs.
Scheme 25
39 was converted into the disodium salt in order to increase its reactivity. After the workup
of the reaction mixture, the majority of the fr1 was recovered, as well as small amounts of
formyl- and diformyl-10-ethyl-phenothiazines. The same failure of the macrocyclization of a
bis(hydroxymethyl)-phenothiazine derivative was reported by Bauer et al. 11
MACROCYCLIZATION REACTION OF 42
42 was subjected to macrocyclization with ditosylated pentaethylene glycole in
acetonitrile using the high-dillution technique (Scheme 36). Cs2CO3 in excess was used as base,
as well as template. The reaction afforded the target macrocycle in good yield (52%).
TsO
N
S
OH 42
OH
O
O
+
O
O
OTs
5 equiv. Cs 2 CO 3 , CH 3 CN
7 days, reflux
52%
Scheme 26
O O
N
S
O
Ts
O O
The product was investigated by MS, NMR and X-ray diffraction. The EI-MS spectrum
presents the molecular peak (M/z = 613). One interesting feature of this macrocyclization is that
after the column chromatography purification no cyclic oligomers were separated.
The 1 H-NMR spectrum presents the peak distribution of the phenothiazine precursor,
and, in addition, the signals characteristic to the pentaethylene glycol chain (protons c,d,e in
Figure 5).
44
O
32

Radu Gropeanu – PhD Thesis Abstract
7.5
7.0
6.5
5'
4'
c
6'
6.0
8
2'
b
a
CH3 H C 2
9
1
N
6
5.5
S
O O
d
O O O O
d
e e e e e e
Figure 5. 1 H-NMR spectrum of 44 (CDCl3, 300 MHz, r.t.)
4
2
2'
5.0
6'
c
5'
4'
c
4.5
d
a b
In the aromatic area the signals were assigned studying the multiplicity, the shape and the
coupling constants (Figure 6).
H4, H6
7.50
20 20
20
H2, H8 H5'
7.40
CDCl 3
7.30
H2', H6'
7.20
41
4.0
5'
4'
c
7.10
6'
8
e
3.5
6
S
7.00
3.0
b
a
CH3 H2C 9
1
N
O O
d
2'
O O O O
d
e e e e e e
H1, H9
4
2
2'
6'
2.5
c
5'
4'
6.90
2.0
18 18
Figure 6. Detail with the aromatic zone of the 1 H-NMR spectrum of 44 (CDCl3, 300 MHz, r.t.)
The solid state molecular structure of 44 was determined by X-rays diffraction analysis of
a monocrystal. In Figure 7 is presented the ORTEP drawing of one molecule.
H4'
1.5
6.80
33

Radu Gropeanu – PhD Thesis Abstract
Figure 7. ORTEP drawing of the X-ray diffraction analysis of a monocrystal of 44
The dihedral angle between the two phenylenes of the phenothiazine core is 133.26°. The
distance between the centroids of the two benzene units is 11.97Å, while the distance between
the sulfur atom and the oxygen atom from the middle of the penta(oxaethylene) chain is 4.97Å.
Taking into consideration that the chain is a little beat twisted, we can assume that the cavity of
the macrocycle 44 has an elliptic shape, with one dimension being the double of the small
dimension.
The unit cell contains four macrocycles (Figure 8), having the (oxaethylene) chains
oriented outside.
Figure 8. Mercury drawing showing the packing of 44 in monocrystal (“wireframe” style)
The packing of these four-macrocycles units generates “empty” rectangle channels (Figure 20).
Two opposite faces of these columns have phenothiazines as “wall tiles”, whilst the other two
opposite faces are delimited by (ethyleneoxa) chains. The distance between two sulphur atoms
belonging to opposite faces is 11.98Å, and the shortest distance between two opposite ethylene
units is 16.22Å.
CONCLUSIONS
The structural analysis of new spiro and dispiro-4[H]-1,3-dioxine derivatives carried out
using NMR spectra and X-ray diffractometry revealed flexible and semiflexible structures and
34

Radu Gropeanu – PhD Thesis Abstract
the cis, trans (compounds 3-8) and the like, unlike (compound 7) isomerism of these derivatives.
The cyclohexane ring prefers the chair conformation, while the 4[H]-1,3-dioxine rings have
chiral half-chair conformations. The investigation of the lattice of 7 showed important stacking
interactions.
The synthesis by an original procedure of a series of new (poly)spiranes containing 1,2dithiolane
rings as cyclic disulfides leads to compounds with flexible or semi-flexible
conformational behaviour, starting from readily available raw materials. The adsorption of some
of these derivatives on a gold surface and the structural behaviour of the resultant 2D-SAMs
were investigated using computational chemistry modelling as well as IR spectroscopy. Despite
the fact that they all appear to adopt a tilted orientation and do not form a well ordered
monolayer, the bidentate cyclic disulfide 32 revealed the possibility to react with both 1,2dithiolane
units, giving rise to a rigid bridge-like conformation. These cyclic disulfides were
effective also in the surface functionalization of gold nanoparticles. These assemblies were
investigated by means of UV-Vis spectroscopy, transmission electron microscopy, and cyclic
voltammetry. Again, 32 has shown interesting properties in functionalization of GNPs (provokes
high aggregation degrees) and in functionalization of gold electrodes with GNPs (the
functionalized electrode with 32 and GNP increased two times the current in cyclic voltammetry,
compared with the bare gold electrode).
During the work in the phenothiazine field, the obtaining of conjugated phenothiazinecontaining
macrocycles was analyzed and pursued.
First, some new valuable iodo-phenothiazine intermediates were obtained and tested in
palladium catalyzed cross-coupling reactions. Despite the difficulties in coupling two richelectron
aromatic systems, the results obtained using the palladium catalyzed cross-couplings,
especially the Negishi coupling involving ferrocene-zincchloride derivatives as intermediates,
opened us the way to achieve the synthesis of phenothiazine-ferrocene containing macrocycles.
Several ferrocene-phenothiazine dyads, triads were synthesized and duly characterized, and some
non-cyclic oligomers by-products were identified. The attempts to synthesize the full-conjugated
bis(ferrocene-phenothiazine) macrocycle have lead to complex mixtures. The ESI-MS
experiments have revealed some small amounts of the desired macrocycle (m/e=930);
unfortunately, this compound could not been isolated in order to perform a full characterization.
The target ferrocene-phenothiazine macrocycle possessing a vinylene bridge was
obtained in good yield using a McMurry reductive coupling of the bis(formyl)ferrocenephenothiazine
triad. The vinylene bridge was selective reduced to an ethylene bridge. In order to
determine the redox properties, the dyads, triads and the macrocycles were subjected to cyclic
voltammetry experiments. An interesting feature of the voltammograms was the non-equivalence
of the phenothiazine moieties in the triads and macrocycles, proving an electronic
communication between these two units. This communication could be established through the
oxidized iron of ferrocene rest or through space, by π-stacking. However, the π-stacking proved
to be important in the solid phase and in macrocycles.
Another class of compounds taken into our attention was the phenothiazine-containing
shape-persistent macrocycles. The synthetic strategy was built on the Sonogashira cross-coupling
reaction between acetylene-derivatives and halo-phenothiazines. The precursors were
synthesized and duly characterized. The macrocyclization main product presents in the MALDI-
TOF measurement the assigned mass for the target macrocycle. Unfortunately, the purity control
using a valuable (i.e. GPC method) and the improvement of the macrocyclization were not
performed.
Another target class of phenothiazine-containing macrocycle was represented by the
phenothiazine-coronands. The desired macrocycles were synthesized in several steps, with the
generation of a dihydroxy-intermediate as the key step. In macrocyclization were used
ditosylated polyethyleneglicole of different lengths as electrophilic partners. The characterization
of these macrocycles was made on the basis of MS, NMR, X-ray diffraction and cyclic
voltammetry.
35

Radu Gropeanu – PhD Thesis Abstract
List of Publications
Published:
1. Sailer, M.; Gropeanu, R.A.;. Müller, T.J.J. “PRACTICAL SYNTHESIS OF IODO
PHENOTHIAZINES. A FACILE ACCESS TO ELECTROPHORE BUILDING BLOCKS”
Journal Of Organic Chemistry 2003, 68, 7509-12.
2. Gropeanu, R.A.; Woiczechowski-Pop, A.; Tintas, M.; Turdean, R.; Grosu, I. “SYNTHESIS
AND STEREOCHEMISTRY OF A NEW SERIES OF 2,2’-DISUBSTITUTED-5,5-
BIS(BROMOMETHYL)-1,3-DIOXANES” Studia Univ. Babes-Bolyai, Ser. Chemia. 2005, L,
247.
Manuscripts:
1. Gropeanu, R.A.; Grosu, I. “SYNTHESIS AND STEREOCHEMISTRY OF SOME NEW
SPIRO BENZO-1,3-DIOXANE DERIVATIVES” Central European Journal of Chemistry 2005,
submitted.
2. Gropeanu, R.A.; Tintas, M.; Pilon, C. ; Morin, M.; Breau, L.; Turdean, R.; Grosu, I.
“SYNTHESIS, STEREOCHEMISTRY AND ADSORPTION STUDIES OF NEW
(POLY)SPIRANES CONTAINING 1,2-DITIOLANE UNITS “Monatshefte für Chemie 2005,
submitted.
Posters:
1. Roiban, D.G., Gropeanu, R.A., Gâz, S.A., Grosu, I. "SPECTROSCOPIC METHODS USED
FOR STRUCTURE INVESTIGATION OF SOME NEW DIOXANES DERIVATIVES", 5th
European Conference on Mineralogy and Spectroscopy (ECMS) in Vienna, Austria, September
4th - 8th 2004
2. Gâz, S. A., Gropeanu, R.A., Roiban, D., Grosu, I. "SYNTHESIS, STEREOCHEMISTRY
AND REACTIVITY OF SOME 2-METHYL-2-(3’-NITROPHENYL)-4-HYDROXYMETHYL-
1,3-DIOXOLANE" 5th European Conference on Mineralogy and Spectroscopy (ECMS) in
Vienna, Austria, September 4th - 8th 2004
36